title: HSP27 regulates IL-1 stimulated IKK activation through interacting with TRAF6 and affecting its ubiquitination.
abstract: Heat shock protein 27 (HSP27) is an ubiquitiously expressed protein, which has been mediated in various biological functions. Here, we present a novel mechanism utilized by HSP27 in regulating IL-1beta induced NF-small ka, CyrillicB activation. Both over-expression and RNAi experiments indicate that HSP27 physically interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6) and promotes TRAF6 ubiquitination. Over-expressed HSP27 augments IL-1beta induced TRAF6 ubiquitination and Ismall ka, CyrillicB kinase (IKK) activation. On the other hand, IL-1beta stimulation reduces endogenous HSP27/TRAF6 association, but inhibiting HSP27 phosphorylation by using SB202190, an inhibitor of p38, and MAPKAPK2 RNAi increases HSP27/TRAF6 association and thereby enhances TRAF6 ubiquitination, IKK phosphorylation as well as NF-small ka, CyrillicB activation. Furthermore, co-transfection study shows that HSP27 S78/82A, two phosphorylated serine site deficient mutants, but not wild-type HSP27 (HSP27 WT) and HSP27 S15A mutant increases TRAF6 ubiquitination and thereby mediates IL-1beta triggered IKK phosphorylation. Taken together, our data indicate that HSP27 regulates IL-1beta triggered NF-small ka, CyrillicB activation via a feedback loop which includes the interaction between HSP27 phosphorylation and ability of HSP27 to bind with TRAF6. The findings of this study reveal a novel mechanism by which HSP27 controls cytokine stimulation.
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210046, PR China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wu
authors.forename: Junhong
authors.initials: J
authors.lastname: Liu
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Huang
authors.initials: H
authors.lastname: Huang
authors.forename: Jiayin
authors.initials: J
authors.lastname: Shen
authors.forename: Shuangquan
authors.initials: S
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Yin
mesh_terms: D002460:Cell Line; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism*; D047468:Immunoprecipitation; D053583:Interleukin-1beta / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D055551:HSP27 Heat-Shock Proteins; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2